Process for the synthesis of benzo[b]thiophenes

ABSTRACT

The present invention is directed to new processes for the synthesis of 2-aryl benzo[b]thiophenes.

BACKGROUND OF THE INVENTION

The present invention is directed to new processes for the synthesis ofbenzo[b]thiophenes, in particular 2-arylbenzo [b]thiophenes.

Benzo[b]thiophenes have been prepared by a number of different syntheticroutes. One of the most widely used methods is the oxidative cyclizationof o-mercaptocinnamic acids. This route is limited to the preparation ofbenzo[b]thiophene-2-carboxylates. 2-Phenylbenzo[b]thiophenes areprepared by acid-catalyzed cyclization of 2-phenylthioacetaldehydedialkyl acetals. Unsubstituted benzo[b]thiophenes are prepared bycatalytic condensation of styrene and sulfur. 3-Substitutedbenzo[b]thiophenes are prepared by acid-catalyzed cyclization ofarylthiomethyl ketones; however, this route is limited to thepreparation of 3-alkylbenzo[b]thiophenes. See Campaigne, "Thiophenes andtheir Benzo Derivatives: (iii) Synthesis and Applications," inComprehensive Heterocyclic Chemistry (Katritzky and Rees, eds.), VolumeIV, Part III, 863-934 (1984). 3-Chloro-2-phenylbenzo[b]thiophene isprepared by the reaction of diphenylacetylene with sulfur dichloride.See Barton and Zika, J. Org. Chem., 35, 1729-1733 (1970).Benzo[b]thiophenes have also been prepared by pyrolysis of styrylsulfoxides. However, low yields and extremely high temperatures makethis route unsuitable for production-scale syntheses. See Ando, J. Chem.Soc., Chem. Comm., 704-705 (1975).

One process of the present invention for preparing benzo[b]thiophenesrequires an intermediate sulfenic acid derivative. Sulfenic acids havebeen postulated as key intermediates in a variety of chemical reactions;however, very few examples exist of the isolation of these compounds.See Shelton and Davis, J. Org. Chem. Soc., 89(3), 718-719 (1968) andDavis et al., J. Org. Chem. Soc., 100, 2844 (1978). Sulfenic acids havebeen generated in situ, and intramolecularly or intermolecularlycyclyzed with olefins and acetylenes. See Mazzanti et al., J. Chem.Soc., Perkin Trans. I, 3299-3004 (1944) and Davis et al., J. Org. Chem.,45, 1650-1653 (1980). A series of trimethylsilyl arenesulfenates havebeen prepared from the coresponding N-benzylidenearenesulfinamides;however, the yield of the trimethylsilyl ester was generally very low.Davis et al., J. Org. Chem., 45, 1650-1653 (1980).

The preparation of 6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophenes wasdescribed in U.S. Pat. Nos. 4,133,814 and 4,380,635. One processdescribed in these patents is the acid-catalyzed intramolecularcyclization/rearrangement ofα-(3-methoxyphenylthio)-4-methoxyacetophenone. The reaction of thisstarting compound in neat polyphosphoric acid at about 85° C. to about90° C. gives an approximate 3:1 mixture of two regioisomeric products:6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and4-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene. These isomericbenzo[b]thiophenes co-precipitate from the reaction mixture, producing amixture containing both compounds. To obtain a single regioisomer, theregioisomers must be separated, such as by chromatography or fractionalcrystallization. Therefore, there currently exists a need for anefficient and regiospecific synthesis of 2-arylbenzo[b]thiophenes fromreadily available starting materials.

SUMMARY OF THE INVENTION

The present invention is directed to processes for the synthesis ofbenzo[b]thiophenes. Specifically, the present invention is directed to aprocess for preparing a compound of the formula ##STR1## wherein:

R₁ is hydrogen, C₁ -C₄ alkoxy, arylalkoxy, halo, or amino; and

R₂ is hydrogen, C₁ -C₄ alkoxy, arylalkoxy, halo, or amino; whichcomprises cyclizing in the presence of an acid catalyst a compound ofthe formula ##STR2## wherein:

R₁ and R₂ are as defined above;

R₄ is OSi(R)₃, NR₅ R₆, or SR₈ ;

each R is independently C₁ -C₆ alkyl, aryl, or arylalkyl;

R₅ and R₆ are independently hydrogen, C₁ -C₆ alkyl, arylalkyl, or aryl,or R₅ and R₆ together with the nitrogen atom form a ring selected frompiperidine, pyrrolidine, morpholine, or hexamethylimine; and

R₈ is C₁ -C₆ alkyl, aryl, or arylalkyl.

Another aspect of the present invention is a second process for thesynthesis of benzo[b]thiophenes. Specifically, the present invention isdirected to a process for preparing a compound of the formula ##STR3##wherein:

R₁ is hydrogen, C₁ -C₄ alkoxy, arylalkoxy, halo, amino; and

R₂ is hydrogen, C₁ -C₄ alkoxy, arylalkoxy, halo, amino; which comprisingtreating a compound of the formula ##STR4## wherein R₁ and R₂ are asdefined above, with an acid catalyst. The present invention is alsodirected to the formula VI compounds, as well as, processes for theirpreparation.

Another aspect of the present invention is a process for the synthesisof a compound of the formula ##STR5## wherein:

R₉ is hydrogen, halo, amino, or hydroxyl;

R₁₀ is hydrogen, halo, amino, or hydroxyl;

R₁₁ and R₁₂ are independently C₁ -C₄ alkyl, or R₁₁ and R₁₂ together withthe adjacent nitrogen atom form a heterocyclic ring selected from thegroup consisting of pyrrolidino, piperidino, hexamethyleneimino, andmorpholino; and

HX is HCl or HBr; comprising the steps of:

(a) cyclizing in the presence of an acid catalyst a compound of theformula ##STR6## wherein:

R₁ is hydrogen, C₁ -C₄ alkoxy, arylalkoxy, halo, or amino;

R₂ is hydrogen, C₁ -C₄ alkoxy, arylalkoxy, halo, or amino; and

R₄ is OSi(R)₃, NRSR₆, or SR₈ ;

each R is independently C₁ -C₆ alkyl, aryl, or arylalkyl;

R₅ and R₆ are independently hydrogen, C₁ -C₆ alkyl, or aryl, or R₅ andR₆ together with the nitrogen atom form a ring selected from piperidine,pyrrolidine, morpholine, and hexamethylimine; and

R₈ is C₁ -C₆ alkyl, aryl, or arylalkyl; to prepare a benzothiophenecompound of the formula ##STR7## wherein R₁ and R₂ are as defined above;

(b) acylating said benzothiophene compound with an acylating agent ofthe formula ##STR8## wherein:

R₁₁, R₁₂, and HX are as defined previously; and

R₁₃ is chloro, bromo, or hydroxyl; in the presence of BX'₃, wherein X'is chloro or bromo;

(c) when R₁ and/or R₂ is C₁ -C₄ alkoxy or arylalkoxy, dealkylating oneor more phenolic groups of the acylation product of step (b) by reactingwith additional BX'₃, wherein X' is as defined above; and

(d) isolating the formula XIII compound;

DETAILED DESCRIPTION OF THE INVENTION

The term "acid catalyst" represents a Lewis acid or a Br.o slashed.nstedacid. Representative Lewis acids are zinc chloride, zinc iodide,aluminum chloride, and aluminum bromide. Representative Br.oslashed.nsted acids include: inorganic acids, such as sulfuric andphosphoric acids; carboxylic acids, such as acetic and trifluoroceticacids; sulfonic acids, such as methanesulfonic, benzenesulfonic,1-naphthalenesulfonic, 1-butanesulfonic, ethanesulfonic,4-ethylbenzenesulfonic, 1-hexanesulfonic, 1,5-naphthalenedisulfonic,1-octanesulfonic, camphorsulfonic, trifluoromethanesulfonic, andp-toluenesulfonic acids; and polymeric arylsulfonic acids, such asNafion®, Amberlyst®, or Amberlite®. The preferred acids for use incatalyzing the processes of the present invention are sulfonic orpolymeric sulfonic acids. More preferably, the acid catalysts aresulfonic acids, such as methanesulfonic acid, benezenesulfonic acid,camphorsulfonic acid, and p-toluenesulfonic acid. The most preferredacid catalyst is p-toluenesulfonic acid.

In the above formula, the term "C₁ -C₄ alkoxy" represents groups such asmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and likegroups. The term "halo" refers to fluoro, chloro, bromo, or iodo groups.

The term "C₁ -C₆ alkyl" represents a straight or branched alkyl chainhaving from one to six carbon atoms. Typical C₁ -C₆ alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,t-butyl, n-pentyl, isopentyl, n-hexyl, 2-methylpentyl, and the like. Theterm "C₁ -C₄ alkyl" represents a straight or branched alkyl chain havingfrom one to four carbon atoms, and includes methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, i-butyl, and t-butyl.

The term "aryl" represents groups such as phenyl and substituted phenyl.The term "substituted phenyl" represents a phenyl group substituted withone or more moieties chosen from the group consisting of halo, hydroxy,nitro, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, trichloromethyl, andtrifluoromethyl. Examples of a substituted phenyl group include4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl,3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl,3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl,4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, 3-nitrophenyl,4-nitrophenyl, 2,4-dinitrophenyl, 4-methylphenyl, 4-ethylphenyl,4-methoxyphenyl, 4-propylphenyl, 4-n-butylphenyl, 4-t-butylphenyl,3-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6-difluorophenyl,2,6-dimethylphenyl, 2-fluoro-5-methylphenyl, 2,4,6-trifluorophenyl,2-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl,3,5-bis(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,3,5-dimethoxyphenyl, 4-hydroxy-3-methylphenyl, 3,5-dimethyl,4-hydroxyphenyl, 2-methyl-4-nitrophenyl, 4-methoxy-2-nitrophenyl, andthe like.

The term "arylalkyl" represents a C₁ -C₄ alkyl group bearing one or morearyl groups. Representatives of this group include benzyl,o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl (such as p-chlorobenzyl,p-bromobenzyl, p-iodobenzyl), 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, 4-phenylbutyl, 2-methyl-2-phenylpropyl,(2,6-dichlorophenyl)methyl, bis(2,6-dichlorophenyl)methyl,(4-hydroxyphenyl)methyl, (2,4-dinitrophenyl)methyl, diphenylmethyl,triphenylmethyl, (p-methoxyphenyl)diphenylmethyl,bis(p-methoxyphenyl)methyl, bis(2-nitrophenyl)methyl, and the like.

The term "arylalkoxy" represents a C₁ -C₄ alkoxy group bearing one ormore aryl groups. Representatives of this group include benzyloxy,o-nitrobenzyloxy, p-nitrobenzyloxy, p-halobenzyloxy (such asp-chlorobenzyloxy, p-bromobenzyloxy, p-iodobenzyloxy), 1-phenylethoxy,2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy,2-methyl-2-phenylpropoxy, (2,6-dichlorophenyl)methoxy,bis(2,6-dichlorophenyl)methoxy, (4-hydroxyphenyl)methoxy,(2,4-dinitrophenyl)methoxy, diphenylmethoxy, triphenylmethoxy,(p-methoxyphenyl)diphenylmethoxy, bis(p-methoxyphenyl)methoxy,bis(2-nitrophenyl)methoxy, and the like.

The term "thermally-labile or acid-labile C₂ -C₁₀ alkyl, C₄ -C₁₀alkenyl, or aryl(C₁ -C₁₀ alkyl) group" represents a group that isreadily removed from the sulfoxide (SO) group under heating or bytreatment with the acid catalyst. The thermally-labile or acid-labile C₂-C₁₀ alkyl groups are straight or branched alkyl chains having from twoto ten carbon atoms and having at least one beta-hydrogen atom.Representative thermally-labile or acid-labile C₂ -C₁₀ alkyl groupsinclude ethyl, n-propyl, i-propyl, 1,1-dimethylpropoyl, n-butyl,sec-butyl, t-butyl, 1,1-dimethylbutyl, 2-methylbutyl, 3-methylbutyl,1-methylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,4-dimethylbutyl,3,3-dimethylbutyl, n-pentyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, n-hexyl, and the like. Thethermally-labile or acid-labile C₄ -C₁₀ alkenyl groups are straight orbranched alkenyl chains having from four to ten carbon atoms, at leastone site of unsaturation, and either a beta-hydrogen or delta-hydrogenatom. Representative thermally-labile or acid-labile C₄ -C₁₀ alkenylgroups include 2-butenyl, 3-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 2-methyl-3-butenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl,4-methyl-2-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,4-methyl-3-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,4-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and thelike. The term thermally-labile or acid-labile aryl(C₁ -C₁₀ alkyl)represents thermally-labile or acid-labile C₂ -C₁₀ alkyl groupsadditionally containing one or more aryl groups and aryl-substitutedmethyl groups. Representative aryl(C₁ -C₁₀ alkyl) groups include benzyl,diphenylmethyl, triphenylmethyl, p-methoxybenzyl, 2-phenylethyl,2-phenylpropyl, 3-phenylpropyl, and the like.

The formula III compounds exist in two regioisomeric forms: the E isomerand the Z isomer. The process of the the present invention usesindividually the E and Z isomers, or mixtures thereof, of the formulaIII compounds. These E and Z regioisomers are represented by thefollowing structures: ##STR9##

One group of compounds that are useful in the processes of the presentinvention are sulfenate silyl esters. In particular, the formula IIIcompounds, where R₄ is OSi(R)₃ and each R is independently C₁ -C₆ alkyl,aryl, or arylalkyl, and the formula IV compounds are silyl esters ofsulfenic acids. The preferred sulfenate silyl esters are abbreviatedusing nomenclature well recognized in the chemical arts, as shown in thefollowing table.

                  TABLE 1                                                         ______________________________________                                        abbreviation    silyl group                                                   ______________________________________                                        TMS             trimethylsilyl                                                TES             triethylsilyl                                                 TIPS            triisopropylsilyl                                             DMIPS           dimethylisopropylsilyl                                        DEIPS           diethylisopropylsilyl                                         TDS             dimethylhexylsilyl                                            TBDMS           t-butyldimethylsilyl                                          TBDPS           t-butyldiphenylsilyl                                          TBS             tribenzylsilyl                                                TPS             triphenylsilyl                                                DPMS            diphenylmethylsilyl                                           TBMPS           t-butyldi(methoxyphenyl)silyl                                 ______________________________________                                    

The term "silylating reagent" represents a compound, or a combination ofcompounds, used to convert the intermediate sulfenic acid to a sulfenatesilyl ester. Representative silylating reagents includebis(trialkylsilyl)ureas, such as 1,3-bis(trimethylsilyl)urea,1,3-bis(triethylsilyl)urea, 1,3-bis (dimethylisopropylsilyl)urea,1,3-bis(triisopropylsilyl)urea, 1,3-bis(diethylisopropylsilyl)urea,1,3-bis(dimethylhexylsilyl)urea, and 1,3-bis(t-butyldimethylsilyl)urea;bis(triarylsilyl)ureas, such as 1,3-bis(triphenylsilyl)urea;bis(diarylalkylsilyl)ureas, such 1,3-bis(diphenylmethylsilyl)urea and1,3-bis(t-butyldiphenylsilyl)urea; and hexaalkyldisilylzanes, such ashexamethyldisilylzane; or combination of a hexaalkyldisilylzane and acatalytic amount of a chlorotrialkylsilane, such aschlorotrimethylsilane.

The starting compounds for the processes of the present invention can beprepared by a number of routes. One method for preparing the formula IIcompounds is shown in Scheme 1. ##STR10##

Generally, a formula VII compound is converted to a styryl sulfide byreaction with a mercaptan of the formula HSR₃ in the presence of a Lewisacid. The formula VIII compound is then oxidized to a styryl sulfoxide,a compound of formula II compound.

More specifically, a formula VII compound, wherein R₁ and R₂ are asdefined above, is treated with a Lewis acid, such as titanium(IV)chloride. This reaction is carried out in an anhydrous organic solvent,such as dry tetrahydrofuran, at a temperature of about 0° C. to about35° C. After about 15 minutes to about one hour, the reaction mixture istreated with an amine base and a mercaptan of the formula HSR₃, where R₃is a thermally-labile or acid-labile C₁ -C₁₀ alkyl, C₄ -C₁₀ alkenyl, oraryl(C₁ -C₁₀ alkyl) group. Preferably, the mercaptan and amine base areadded as a solution in the reaction solvent. A representative amine baseis triethylamine. After the addition of the mercaptan and amine base,the reaction is generally heated to a temperature of about 35° C. toabout 65° C., preferably at about 50° C. The products of this reactioncan be purified using techniques well known in the chemical arts, suchas by crystallization or chromatography.

The formula VIII compound, where R₁, R₂, and R₃ are as defined above, isthen oxidized to produce the formula II compounds. Suitable oxidizingagents for this reaction are peracids, such as peracetic acid andm-chloroperoxybenzoic acid, and hydrogen peroxide. This oxidationreaction is typically run in an organic solvent, such as toluene,methylene chloride, chloroform, or carbon tetrachloride. When a peracidis used as the oxidant, the reaction is generally carried out at atemperature of about -30° C. to about 15° C., preferably at about -20°C. The products of the reaction are easily purified byrecrystallization. When R₃ is t-butyl, the crystalline product of thisreaction sequence is the E regioisomer of formula II.

When R₃ has a tertiary carbon adjacent to the sulfur atom, the Zregioisomer of the formula II compounds can be prepared selectively by asecond route as shown in Scheme II. ##STR11##

Generally, a benzyl alcohol, a formula IX compound, is reacted with amercaptan of the formula R₃ SH to produce a benzyl sulfide, a formula Xcompound. This benzyl sulfide is reacted with a strong base, forming abenzylic anion, which is condensed with a benzaldehyde. Thiscondensation product is reacted with an acid chloride and the resultingintermediate treated with a second strong base to produce a styrylsulfide, a formula VIIIZ compound. This styryl sulfide is then oxidizedwith an oxidizing agent to produce the formula IIZ compound.

The first step in the synthesis of the Z styryl sulfoxide compounds isthe conversion of a benzyl alcohol to a benzyl sulfide, formula Xcompound. The reaction of the formula IX compound, where R₂ is asdefined above, with a mercaptan of the formula R₃ SH, wherein R₃ is athermally-labile or acid-labile C₂ -C₁₀ alkyl, C₄ -C₁₀ alkenyl, oraryl(C₁ -C₁₀ alkyl) group having a tertiary carbon atom adjacent to thesulfur atom, in the presence of a Lewis acid produces the benzylsulfide, a formula X compound. Suitable Lewis acids for thistransformation are zinc bromide, zinc chloride, zinc iodide, ferricchloride, titanium(IV) chloride, aluminum trichloride, and aluminumtribromide, preferably zinc iodide. The reaction is generally carriedout in an organic solvent, such as 1,2-dichloroethane or methylenechloride. When the reaction is carried out at room temperature, thereaction is complete after about 18 hours.

The benzyl sulfide is reacted with a strong base to form a benzylicanion. Suitable strong bases for this reaction include metal alkoxides,such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithiumt-butoxide, and potassium t-butoxide; sodium hydride; and alkyllithiums,such as n-butyllithium, t-butyllithium, sec-butyllithium, andmethyllithium. The preferred strong base for this reaction isn-butyllithium. The preferred solvent for this reaction is drytetrahydrofuran. When n-butyllithium is used as the strong base, thereaction is carried out at a temperature of about -35° C. to about -15°C.

The benzylic anion is condensed with a benzaldehyde to prepare anintermediate condensation product. The benzaldehyde has the generalformula p-R₁ (C₆ H₄)CHO, wherein R₁ is hydrogen, C₁ -C₄ alkoxy,arylalkoxy, halo, or amino. Preferably, the benzylic anion is preparedand the condensation product is formed in situ by adding thebenzaldehyde to the cold solution of the benzylic anion.

The condensation product is treated with an acid chloride to produce anintermediate compound. Representative acid chlorides include acylchlorides, such as acetyl chloride and benzoyl chloride; sulfonylchlorides, such as methanesulfonyl chloride, benzenesulfonyl chloride,1-butanesulfonyl chloride, ethanesulfonyl chloride, isopropylsulfonylchloride, and p-toluenesulfonyl chloride; alkoxycarbonyl chlorides, suchas methoxycarbonyl chloride and benzyloxycarbonyl chloride; anddialkylaminocarbonyl chlorides, such as N,N-dimethylaminocarbonylchloride; preferably a sulfonyl chloride. Preferably, methanesulfonylchloride is added to the reaction mixture shortly after formation of thecondensation product.

This intermediate compound is reacted with a second strong base toproduce a styryl sulfide, a formula VIIIZ compound where R₁, R₂, and R₃are as defined above. Suitable strong bases for this reaction includemetal alkoxides, such as sodium methoxide, sodium ethoxide, lithiumethoxide, lithium t-butoxide, and potassium t-butoxide; sodium hydride;alkyllithiums, such as n-butyllithium, t-butyllithium, sec-butyllithium,and methyllithium; and metal amides, such as sodium amide, magnesiumdiisopropylamide, and lithium diisopropylamide. The preferred strongbase for this reaction is potassium t-butoxide. Generally, this reactionis carried out at about 15° C. to about room temperature, preferably atroom temperature.

The styryl sulfide is oxidized to prepare the corresponding styrylsulfoxide. Suitable oxidizing agents for this reaction are peracids,such as peracetic acid and m-chloroperoxybenzoic acid; organicperoxides, such as t-butyl peroxide; and hydrogen peroxide. Preferablythe oxidizing agent is peracetic acid. This oxidation is typicallycarried out in an organic solvent, such as toluene, benzene, xylene,methanol, ethanol, methylacetate, ethylacetate, methylene chloride,1,2-dichloroethane, or chloroform; preferably methylene chloride. Thisoxidation can be carried out at a temperature of about -40° C. to about0° C.

Alternatively, when R₃ has a tertiary carbon adjacent to the sulfuratom, the benzyl sulfide intermediate (formula X compound) can be usedto produce a mixture of E and Z isomers of the styryl sulfoxides, theformula II compounds. This synthesis is outlined is Scheme 3. ##STR12##

The benzyl sulfide, prepared as described above, is oxidized to producethe corresponding benzyl sulfoxide. This benzyl sulfoxide is reactedwith a strong base, and the resulting anion condensed with abenzaldehyde. The condensation product is reacted with an acid chlorideand the resulting intermediate compound reacted with a second strongbase to produce the styryl sulfoxide.

The benzyl sulfide, the formula X compound, wherein R₂ is as definedabove and R₃ is a thermally-labile or acid-labile C₂ -C₁₀ alkyl, C₄ -C₁₀alkenyl, or aryl(C₁ -C₁₀ alkyl) group having a tertiary carbon atomadjacent to the sulfur atom, is oxidized to produce the correspondingbenzyl sulfoxide, formula XI compound. Suitable oxidizing agents forthis reaction are peracids, such as peracetic acid andm-chloroperoxybenzoic acid; organic peroxides, such as t-butyl peroxide;and hydrogen peroxide. Preferably the oxidizing agent is peracetic acid.This oxidation is typically carried out in an organic solvent, such astoluene, benzene, xylene, methanol, ethanol, methylacetate,ethylacetate, methylene chloride, 1,2-dichloroethane, or chloroform;preferably at a temperature of about -30° C. to about 5° C.

The benzyl sulfoxide, formula XI compound wherein R₂ and R₃ are asdefined above, is reacted with a strong base to produce a benzylicanion. Suitable strong bases for this reaction include metal alkoxides,such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithiumt-butoxide, and potassium t-butoxide; sodium hydride; alkyllithiums,such as n-butyllithium, t-butyllithium, sec-butyllithium, andmethyllithium; and metal amides, such as sodium amide, magnesiumdiisopropylamide, and lithium diisopropylamide. The preferred base forthis transformation is n-butyllithium. This deprotonation reaction iscarried out in a dry organic solvent, such as tetrahydrofuran or1,2-dimethoxyethane, at a temperature of about -25° C.

The benzylic anion is condensed, without isolation, with a benzaldehydecompound of the formula p-R₁ (C₆ H₄)CHO, wherein R₁ is as defined above.Preferably, about one equivalent of the benzaldehyde is added to thecold solution prepared as described in the preceding paragraph. Theresulting diastereomeric mixture of condensation products may beisolated, or preferably used in the next step without isolation.

The condensation product is reacted with an acid chloride to produce anintermediate compound. The condensation product is optionally treatedwith a base, such as n-butyllithium, and reacted with an acid chloride.Representative acid chlorides include acyl chlorides, such as acetylchloride and benzoyl chloride; sulfonyl chlorides, such asmethanesulfonyl chloride, benzenesulfonyl chloride, 1-butanesulfonylchloride, ethanesulfonyl chloride, isopropylsulfonyl chloride, andp-toluenesulfonyl chloride; alkoxycarbonyl chlorides, such asmethoxycarbonyl chloride and benzyloxycarbonyl chloride; anddialkylaminocarbonyl chlorides, such as N,N-dimethylaminocarbonylchloride; preferably a sulfonyl chloride. The acid chloride is added tothe cold reaction mixture, then the resulting mixture is allowed to warmto room temperature. Preferably, methanesulfonyl chloride is added tothe reaction mixture shortly after formation of the condensationproduct, which eliminates the need to add additional base.

The resulting intermediate compound is reacted with a second strong baseto produce the E and Z styryl sulfoxides, formula II compounds where R₁,R₂, and R₃ are as defined above. Representative second strong bases forthis elimination reaction include metal alkoxides, such as sodiummethoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide, andpotassium t-butoxide; sodium hydride; alkyllithiums, such asn-butyllithium, t-butyllithium, sec-butyllithium, and methyllithium; andmetal amides, such as sodium amide, magnesium diisopropylamide, andlithium diisopropylamide. The preferred base for this transformation ispotassium t-butoxide. Preferably, a 20% excess, such as 1.2 equivalents,of the second base are added. Generally, this reaction is carried out ata temperature of about 15° C. to about room temperature, preferably atroom temperature.

The compounds of the present invention can be prepared from the formulaII compounds. The novel sulfenate silyl esters are prepared from thestyryl sulfoxides as shown in Scheme 4. ##STR13##

Generally, the sulfenate silyl esters, where R₁, R₂, and R₇ are asdefined above and R₃ is a thermally-labile or acid-labile C₁ -C₁₀ alkyl,C₄ -C₁₀ alkenyl, or aryl(C₁ -C₁₀ alkyl) group, are prepared by reactinga formula II compound with a silylating reagent. Suitable solvents forthis reaction include benzene, toluene, xylene, and high-boiling,halogenated hydrocarbon solvents, having a boiling point greater than orequal to 80° C., such as 1,1,2-trichloroethane. Suitable silylatingreagents include bis(trialkylsilyl)ureas, such as1,3-bis(trimethylsilyl)urea, 1,3-bis(triethylsilyl)urea,1,3-bis(dimethylisopropylsilyl)-urea,1,3-bis(t-butyl-dimethylsilyl)urea; bis(triarylsilyl)-ureas, such as1,3-bis(triphenylsilyl)urea; bis(dialkylarylsilyl)ureas, such1,3-bis(diphenylmethylsilyl)urea; and hexaalkyldisilylzanes, such ashexamethyldisilylzane; or combination of a hexaalkyldisilylzane and acatalytic amount of a chlorotrialkylsilane, such aschlorotrimethylsilane. For best results, the final concentration, aftercomplete addition, of the formula II compound is about 0.001M to about0.5M. Preferably, a slight excess, such as ten percent, of thesilylating reagent is used. This reaction can be carried out at about80° C. to about 140° C. for about ten minutes to about two hours.Because the Z isomer reacts much faster than the corresponding E isomer,the use of only the Z isomer as the starting compound requires less timefor complete transformation.

The novel sulfenamides are prepared from the sulfenate silyl esters asshown in Scheme 5. ##STR14##

Generally, the sulfenate silyl ester, where R₁, R₂, and R₇ are asdefined above, is prepared from the styryl sulfoxide and, preferablywithout isolation or purification, reacted with an amine of the formulaHNR₅ BR₆, wherein R₅ and R₆ as defined above. Typically, the sulfenatesilyl ester is prepared, the reaction solution cooled to about 0° C. toabout 50° C., and treated with the amine. Preferably, one to twoequivalents of the amine are used. The conversion from the silyl esterto the sulfenamide is typically complete after about two hours to abouteight hours. The resulting sulfenamides can be purified using standardorganic techniques, such as silica-gel chromatography.

The novel disulfides are prepared from the sulfenate silyl esters asshown in Scheme 6. ##STR15##

Generally, the sulfenate silyl ester, where R₁, R₂, and R₇ are asdefined above, is prepared from the styryl sulfoxide and, preferablywithout isolation or purification, reacted with a mercaptan of theformula HSR₈, where R₈ is as defined above, in the presence of an aminebase. Preferably, the sulfenate silyl ester is prepared, the reactionsolution allowed to cool to room temperature, and the reaction mixturetreated with a solution containing the mercaptan and amine base. Thesolvent for this mercaptan/amine solution is the same as the solvent forthe sulfenate silyl ester-containing mixture. Representative amine basesinclude triethylamine, diisopropylethylamine, pyridine, morpholine,N-methylmorpholine, and collidine. The conversion of the sulfenate silylester is typically complete after about one to about eight hours. Theresulting disulfides can be purified using standard organic techniques,such as silica-gel chromatography.

The intermediate sulfenate silyl esters, sulfenamides, and disulfidesare useful for the synthesis of 2-arylbenzo[b]thiophenes as shown inScheme 7. ##STR16##

Generally, the sulfenate silyl esters, sulfenamides, or disulfides aretreated with acid catalysts to produce the formula I compounds. Suitableacid catalysts for this reaction include Lewis acids or Br.oslashed.nsted acids. Representative Lewis acids include zinc chloride,zinc iodide, aluminum chloride, and aluminum bromide. RepresentativeBr.o slashed.nsted acids include inorganic acids, such as sulfuric andphosphoric acids; carboxylic acids, such as acetic and trifluoroaceticacids; sulfonic acids, such as methanesulfonic, benzenesulfonic,1-naphthalenesulfonic, 1-butanesulfonic, ethanesulfonic,4-ethylbenzenesulfonic, 1-hexanesulfonic, 1,5-naphthalenedisulfonic,1-octanesulfonic, camphorsulfonic, trifluoromethanesulfonic, andp-toluenesulfonic acids; and polymeric arylsulfonic acids, such asNafion®, Amberlyst®, or Amberlite®. The more preferred acid catalystsare sulfonic acids, such as methanesulfonic acid, benezene-sulfonicacid, camphorsulfonic, and p-toluenesulfonic acid. The most preferredacid catalyst is p-toluenesulfonic acid. Typically, a solution of theacid catalyst in an organic solvent, such as toluene, benzene, xylene,or a high-boiling halogenated hydrocarbon solvent, such as1,1,2-trichloroethane, is heated to about 80° C. to about 140° C., andtreated with a solution of the sulfenate silyl ester, sulfenamide, ordisulfide in the same solvent. An excess amount of the acid catalyst isused, preferably three equivalents of the acid. For best results, thefinal concentration of the starting compound is about 0.01M to about0.2M, preferably 0.05M. Furthermore, best yields are obtained when thesulfenate silyl ester is slowly added to the heated acid solution over aperiod of about 15 minutes to about three hours. For best results,residual water is removed from the reaction solution by the use of aDean-Stark trap or Soxhlet extractor.

The styryl sulfoxides are also useful for the preparation of abenzothiophene styryl sulfide as shown in Scheme 8. ##STR17##

These benzothiophene styryl sulfides, where R₁ and R₂ are as definedabove, are prepared from the styryl sulfoxides. Generally, a solution ofthe styryl sulfoxide, where R₁ and R₂ are as defined above and R₃ is athermally-labile or acid-labile C₂ -C₁₀ alkyl, C₄ -C₁₀ alkenyl, oraryl(C₁ -C₁₀ alkyl) group, is added to a solution of an acid catalyst ata temperature of about 100° C. to about 140° C., where the acid catalystis defined above. The concentration of acid catalyst is dependent on thefinal concentration of the formula II compound and the rate of additionof the formula II compound. When the styryl sulfoxide is at a finalconcentration of about 0.2M and is added over six hours, the acidconcentration is about 0.002M. When the styryl sulfoxide is at a finalconcentration of about 0.05M and is added over 30 minutes, the acidconcentration is about 0.025M. Significant quantities of the formula VIcompounds are present in the reaction after about one to two hours.Longer reaction times lead to the production of the formula I compounds.

These formula VI compounds may be subsequently converted to the formulaI compounds by treatment with additional acid, such as about 0.5 toabout three equivalents, and heating to about 100° C. to about 140° C.The concentration of the formula VI compound is in the range of about0.01M to about 0.5M. Suitable solvents for both the formation of theformula VI compounds and their conversion to formula I compounds includetoluene, xylene, and 1,2-dichloroethane.

The formula I compounds are useful as intermediates in the synthesis ofa series of 3-aroyl-2-arylbenzo[b]thiophenes. U.S. Pat. Nos. 4,133,814and 4,418,068, which are incorporated herein by reference, describedthese 3-aroyl-2-arylbenzo[b]thiophenes, as well as methods for theirpreparation from the formula I compounds. An improved synthesis of agroup of these 3-aroyl-2-arylbenzo[b]thiophenes from the formula Icompounds, wherein R₁ and R₂ are hydrogen, C₁ -C₄ alkoxy, or arylalkoxyis outlined in Scheme 9. ##STR18##

The Formula I compound, wherein R₁ and R₂ are hydrogen, C₁ -C₄ alkoxy,or arylalkoxy, is acylated with the formula XII compound, wherein R₁₃ ischloro or hydroxy, in the presence of boron trichloride or borontribromide; boron trichloride is preferred. The reaction can be carriedout in a variety of organic solvents, such as chloroform, methylenechloride, 1,2-dichloroethane, 1,2,3-dichloropropane,1,1,2,2-tetrachloroethane, 1,2-dichlorobenzene, chlorobenzene, andfluorobenzene. The preferred solvent for this synthesis is1,2-dichloroethane. The reaction is carried out at a temperature ofabout -10° C. to about 25° C., preferably at 0° C. The reaction is bestcarried out at a concentration of the benzothiophene formula I compoundof about 0.2M to about 1.0M. The acylation reaction is generallycomplete after about two hours to about eight hours.

When R₁ and/or R₂ is a C₁ -C₄ alkoxy or arylalkoxy group, the acylatedbenzothiophene preferably is converted to a formula XIII compound,wherein R₅ and/or R₆ are hydroxy, without isolation of the product fromthe acylation reaction. This conversion is performed by addingadditional boron trichloride or boron tribromide and heating thereaction mixture. Preferably, two to five molar equivalents of borontrichloride are added to the reaction mixture, most preferably threemolar equivalents. This reaction is carried out at a temperature ofabout 25° C. to about 40° C., preferably at 35° C. The reaction isgenerally complete after about 4 hours to about 48 hours.

The acylation reaction or acylation/dealkylation reaction is quenchedwith an alcohol or a mixture of alcohols. Suitable alcohols for use inquenching the reaction include methanol, ethanol, and isopropanol.Preferably, the acylation/dealkylation reaction mixture is added to a95:5 mixture of ethanol and methanol (3A ethanol). The 3A ethanol can beat room temperature or heated to reflux, preferably at reflux. When thequench is performed in this manner, the Formula XIII compoundconveniently crystallizes from the resulting alcoholic mixture.Generally, 1.25 mL to 3.75 mL of alcohol per millimole of thebenzothiophene starting material are used.

The following examples further illustrate the present invention. Theexamples are not intended to be limiting to the scope of the inventionin any respect, and should not be so construed. All experiments were rununder positive pressure of dry nitrogen. All solvents and reagents wereused as obtained. The percentages are generally calculated on a weight(w/w) basis; except for high performance liquid chromatography (HPLC)solvents which are calculated on a volume (v/v) basis. Proton nuclearmagnetic resonance (¹ H NMR) spectra and ¹³ C nuclear magnetic resonance(¹³ C NMR) spectra were obtained on a Bruker AC-300 FTNMR spectrometerat 300.135 MHz or at 75.469 MHz for proton and carbon, respectively, ora GE QE-300 spectrometer at 300.15 MHz. Silica-gel flash chromatographywas performed as described by Still et al. using Silica Gel 60 (230-400mesh, E. Merck). Still et al., J. Org. Chem., 43, 2923 (1978). Elementalanalyses for carbon, hydrogen, and nitrogen were determined on a ControlEquipment Corporation 440 Elemental Analyzer. Elemental analyses forsulfur were determined on a Brinkman Colorimetric Elemental Analyzer.Melting points were determined in open glass capillaries on a Mel-TempII melting point apparatus or a Mettler FP62 Automatic instrument, andare uncorrected. Field desorption mass spectra (FDMS) were obtainedusing a Varian Instruments VG 70-SE or VG ZAB-3F mass spectrometer. Highresolution free atom bombardment mass spectra (FABMS) were obtainedusing a Varian Instruments VG ZAB-2SE mass spectrometer.

The in situ yields of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophenewere determined by high performance liquid chromatography (HPLC) incomparison to an authentic sample of this compound prepared by publishedsynthetic routes. See U.S. Pat. No. 4,133,814. Generally, samples of thereaction mixture was diluted with acetonitrile and the diluted sampleassayed by HPLC using a Zorbax® RX-C8 column (4.6 mm×25 cm) with UVdetection (280 nm). The following linear-gradient solvent system wasused for this analysis:

    ______________________________________                                        Gradient Solvent System                                                       Time (min)      A (%)   B (%)                                                 ______________________________________                                         0              50      50                                                     2              50      50                                                    20              20      80                                                    35              20      80                                                    37              50      50                                                    45              50      50                                                    ______________________________________                                         A: 0.01 M aqueous sodium phosphate (pH 2.0)                                   B. acetonitrile                                                          

The amount (percentages) of6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophenehydrochloride in the crystalline material (potency) was determined bythe following method. A sample of the crystalline solid (5 mg) wasweighed into a 100 mL volumetric flask, and dissolved in a 70/30 (v/v)mixture of 75 mM potassium phosphate buffer (pH 2.0) and acetonitrile.An aliquot of this solution (10 μL) was assayed by high performanceliquid chromatography, using a Zorbax® Rx-C8 column (25 cm×4.6 mm ID, 5μparticle) and UV detection (280 nm). The following gradient solventsystem was used:

    ______________________________________                                        Gradient Solvent System (Potency)                                             Time (min)      A (%)   B (%)                                                 ______________________________________                                         0              70      30                                                    12              70      30                                                    14              25      75                                                    16              70      30                                                    25              70      30                                                    ______________________________________                                         A: 75 mM KH.sub.2 PO.sub.4 buffer (pH 2.0)                                    B: acetonitrile                                                          

The percentage of6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophenehydrochloride in the sample was calculated using the peak area, slope(m), and intercept (b) of the calibration curve with the followingequation: ##EQU1##

The amount (percentage) of solvent, such as 1,2-dichloroethane, presentin the crystalline material was determined by gas chromatography. Asample of the crystalline solid (50 mg) was weighed into a 10 mLvolumetric flask, and dissolved in a solution of 2-butanol (0.025 mg/mL)in dimethylsulfoxide. A sample of this solution was analyzed on a gaschromatograph using a DB Wax column (30 m×0.53 mm ID, 1μ particle), witha column flow of 10 mL/min and flame ionization detection. The columntemperature was heated from 35° C. to 230° C. over a 12 minute period.The amount of solvent was determined by comparison to the internalstandard (2-butanol).

EXAMPLE 1 E-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide

A. Preparation of E-t-Butyl 4,4'-Dimethoxystilbenyl Sulfide

A solution of desoxyanisoin (12.82 g) in tetrahydrofuran (100 mL) wastreated with titanium (IV) chloride (10.43 g). During the dropwiseaddition of titanium (IV) chloride, the reaction mixture was cooled tomaintain the temperature below 35° C. Upon complete addition, theresulting mixture was stirred at 30° C. After an additional 30 minutes,this mixture was treated with a solution of 2-methyl-2-propanethiol(6.76 mL) and triethylamine (16.70 mL) in tetrahydrofuran (15 mL). Theresulting mixture was stirred at 50° C. After two hours, the mixture wasadded to ten percent sodium carbonate (500 mL). The resulting mixturewas extracted with methylene chloride. The combined methylene chlorideextracts were dried over magnesium sulfate, filtered, and concentratedin vacuo to give 17.2 g of an oil, which crystallized upon cooling toroom temperature. This crystalline material was recrystallized from hotethanol to give 12.3 g of the title compound. Melting point 71°-73° C.

Analysis calculated for C₂₀ H₂₄ O₂ S: C, 73.13; H, 7.36; S, 9.76. Found:C, 73.37; H, 7.51; S, 9.87.

B. Preparation of E-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide

The crystalline compound prepared as described in Example 1A wasdissolved in toluene (150 mL), and the resulting solution cooled toabout -20° C. The cold solution was treated with peracetic acid (32% w/win dilute acetic acid, 1.24 g) over ten minutes. The resulting mixturewas extracted with saturated sodium sulfite and brine. The organic phasewas concentrated in vacuo. The residue was recrystallized from ethylacetate/heptane to give 14.11 g of the title compound. Melting point104° C. (dec).

Analysis calculated for C₂₀ H₂₄ O₃ S: C, 69.74; H, 7.02; S, 9.31. Found:C, 69.47; H, 7.04; S, 9.54.

EXAMPLE 2 Z-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide

A. Preparation of t-Butyl 4-Methoxybenzyl Sulfide

A mixture of 4-methoxybenzyl alcohol (10.13 g) and zinc iodide (11.7 g)in 1,2-dichloroethane (120 mL) was treated with 2-methyl-2-propanethiol(9.92 mL) in one portion. The resulting mixture was stirred at roomtemperature. After about 18 hours, the reaction was diluted with water(100 mL) and methylene chloride (100 mL). The organic phase was removed,dried over magnesium sulfate, filtered, and concentrated in vacuo togive 14.4 g of an oil.

¹ H NMR (CDCl₃): δ7.28 (d, 2H), 6.85 (d, 2H), 3.77 (s, 3H), 3.73 (s,2H), 1.36 (s, 9H).

¹³ C NMR (CDCl₃): δ130, 114, 56, 35, 32.

Analysis calculated for C₁₂ H₁₈ OS: C, 68.52; H, 8.63. Found: C, 68.80;H, 8.67.

B. Preparation of Z-t-Butyl 4,4'Dimethoxystilbenyl Sulfide

A solution of the compound prepared as described in Example 2A (2.51 g)in tetrahydrofuran (50 mL) was cooled to about -20° C. This coldsolution was treated with a solution of n-butyllithium in hexane (1.6M,7.47 mL) over ten minutes. The resulting solution was allowed to warm toabout 0° C. over 35 minutes. This cold solution was treated withp-anisaldehyde (1.46 mL). After an additional 15 minutes, the reactionsolution was treated with methanesulfonyl chloride (0.95 mL). Theresulting reaction was allowed to warm to room temperature. After anadditional 45 minutes, the reaction mixture was treated with a solutionof potassium t-butoxide in tetrahydrofuran (1.0M, 12.0 mL). After anadditional 45 minutes, the reaction was quenched by the addition of 1Nhydrochloric acid (12.0 mL). The organic phase was separated, dried overmagnesium sulfate, filtered, and concentrated to an oil (4.4 g).

¹ H NMR (CDCl₃): δ7.95 (d, H), 7.05 (s, H), 6.9 (d, H), 6.8 (dd, 2H),3.75 (s, 3H), 0.95 (s, 9H).

¹³ C NMR (CDCl₃): δ153, 139, 137, 114, 56, 32.

C. Preparation of Z-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide

The compound from Example 2B was converted to the title compound usingthe procedure substantially as described in Example 1B.

¹ H NMR (CDCl₃): δ7.61 (d, H), 7.56 (d, H), 7.1 (s, H), 6.9 (dd, 2H),3.83 (s, 3H), 1.05 (s, 9H).

¹³ C NMR (CDCl₃): δ142, 132.5, 131, 118, 117, 56, 24.

Analysis calculated for C₂₀ H₂₄ O₃ S: C, 69.74; H, 7.02. Found: C,69.98; H, 6.94.

EXAMPLE 3 E and Z-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide

A. Preparation of t-Butyl 4-Methoxybenzyl Sulfide

A mixture of 4-methoxybenzyl alcohol (10.13 g) and zinc iodide (11.7 g)in 1,2-dichloroethane (120 mL) was treated with 2-methyl-2-propanethiol(9.92 mL) in one portion. The resulting mixture was stirred at roomtemperature. After about 18 hours, the reaction was diluted with water(100 mL) and methylene chloride (100 mL). The organic phase was removed,dried over magnesium sulfate, filtered, and concentrated in vacuo togive 14.4 g of an oil.

¹ H NMR (CDCl₃): δ7.28 (d, 2H), 6.85 (d, 2H), 3.77 (s, 3H), 3.73 (s,2H), 1.36 (s, 9H).

¹³ C NMR (CDCl₃): δ130, 114, 56, 35, 32.

Analysis calculated for C₁₂ H₁₈ OS: C, 68.52; H, 8.63. Found: C, 68.80;H, 8.67.

B. Preparation of t-Butyl 4-Methoxybenzyl Sulfoxide

A solution of the compound prepared as described in Example 3A (14.4 g)in 1,2-dichloroethane (50 mL) was cooled to about 5° C. and the coldsolution treated with peracetic acid (32% w/w in dilute acetic acid,14.2 mL) over 30 minutes. Upon complete addition of the peracetic acid,the reaction was treated with brine and sodium bicarbonate. The organicphase was removed, dried over magnesium sulfate, filtered, andconcentrated to a yellow precipitate. This residue was treated withhexane (100 mL) and the resulting mixture stirred at room temperature.After about 18 hours, the mixture was filtered and the solids washedwith hexane (100 mL). The solid material was dried in vacuo to give14.07 g of the title compound. Melting point 124°-126° C.

¹ H NMR (CDCl₃): δ7.26 (d, 2H), 6.89 (d, 2H), 3.79 (d, H), 3.78 (s, 3H),3.58 (d, H), 1.3 (s, 9H).

¹³ C NMR (CDCl₃): δ132, 114, 56, 53, 23.

Analysis calculated for C₁₂ H₁₈ O₂ S: C, 63.68; H, 8.02. Found: C,63.72; H, 7.93.

C. Preparation of E and Z-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide

A solution of the compound prepared as described in Example 3B (10.0 g)in tetrahydrofuran (140 mL) was cooled to about -30° to -25° C. (dryice/acetone bath). This cold solution was treated with n-butyllithium incyclohexane (1.6M, 27.65 mL) over 25 minutes. After stirring for 35minutes, the reaction mixture was treated with p-anisaldehyde (5.4 mL).The dry ice/acetone bath was removed and the reaction allowed to warm toabout 20° C. This mixture was treated with methanesulfonyl chloride (3.5mL). The temperature of the reaction rose from about 20° to about 35° C.upon addition of the methanesulfonyl chloride. The mixture was cooled toabout 25° C., then treated with potassium t-butoxide in tetrahydrofuran(1M, 50.9 mL). After stirring for an additional 35 minutes, the reactionwas treated with 1N hydrochloric acid (51.0 mL). The phases wereseparated, and the organic layer dried over magnesium sulfate, filtered,and concentrated to an oil (16.67 g). This material was used in the nextstep without further purification. The carbon and proton NMR spectrawere similar to that obtained for the compound prepared as described inExamples 1 and 2.

EXAMPLE 4 E and Z-Trimethylsilyl 4,4'-Dimethoxystilbenyl Sulfenate

A mixture of the compound prepared as described in Example 1 (350 mg)and 1,3-bis(trimethylsilyl)urea (116 mg) in toluene (11 mL) was heatedto reflux. After 1.5 hours, the reaction mixture was allowed to cool toroom temperature, filtered, and the filtrate concentrated in vacuo togive a 7:1 mixture of E/Z regioisomers of the title compounds.

FDMS: m/z=361 (M+1).

E Isomer: ¹ H NMR (d₆ -benzene): δ7.39 (d, 2H), 7.10 (d, 2H), 6.68 (d,2H), 6.68 (s, 1H), 6.57 (d, 2H), 3.18 (s, 3H), 3.17 (s, 3H), 0.23 (s,9H).

Z Isomer: ¹ H NMR (d₆ -benzene): δ7.71 (d, 2H), 7.31 (d, 2H), 6.85 (d,2H), 6.79 (d, 2H), 6.60 (s, 1H), 3.28 (s, 3H), 3.26 (s, 3H), -0.05 (s,9H).

EXAMPLE 5 E and Z-Trimethylsilyl 4,4'-Dimethoxystilbenyl Sulfenate

A mixture of the compound prepared as described in Example 2 and1,3-bis(trimethylsilyl)urea in toluene was heated to reflux. After tenminutes, the mixture was allowed to cool, filtered, and concentrated invacuo to give a 7:1 mixture of E/Z regioisomers of the title compounds.

E Isomer: ¹³ C NMR (d₆ -benzene, 8° C.): δ160.49, 158.53, 141.54,131.97, 129.91, 129.65, 125.59, 116.41, 114.68, 113.98, 54.56, -0.09.

EXAMPLE 6 E and Z-N,N-Dimethyl-4,4'-Dimethoxystilbenyl Sulfenamide

A mixture of the compound prepared as described in Example 1 (1.74 g)and 1,3-bis(trimethylsilyl)urea (578 mg) in toluene (54 mL) was heatedto reflux. After 1.5 hours, the reaction was allowed to cool to roomtemperature, and treated with dimethylamine (2.80 mL, 2.0M intetrahydrofuran). After an additional two hours, the reaction solutionwas evaporated to dryness to give a 7:1 mixture of E/Z regioisomers ofthe title compounds. This residual mixture was purified using silica-gelflash chromatography, eluting with a mixture of ethyl acetate/hexane(9:1), to give 1.06 g of the title compounds as an 8:1 mixture of E/Zregioisomers.

FDMS: m/z=315 (M⁺).

Analysis calculated for C₁₈ H₂₁ NO₂ S: C, 68.54; H, 6.71; N, 4.44.Found: C, 68.40; H, 6.69; N, 4.22.

E Isomer: ¹ H NMR (d₆ -benzene): δ7.44 (d, 2H), 7.11 (d, 2H), 6.99 (s,1H), 6.71 (d, 2H), 6.56 (d, 2H), 3.22 (s, 3H), 3.18 (s, 3H), 2.66 (s,6H). ¹³ C NMR (d₆ -benzene): δ160.00, 158.83, 139,70, 131.48, 130.78,130.51, 129.94, 123.77, 114.55, 113.97, 54.63, 54.61, 48.17.

Z Isomer: ¹ H NMR (d₆ -benzene): δ7.61 (d, 4H), 6.82 (d, 2H), 6.80 (d,2H), 6.80 (s, 1H), 3.32 (s, 3H), 3.27 (s, 3H), 2.41 (s, 6H). ¹³ C NMR(d₆ -benzene): δ159.89, 159.30, 139.76, 136.46, 131.94, 131.82, 130.22,130.20, 113.83, 113.76, 54.81, 54.73, 48.61.

EXAMPLE 7 E and Z-N-Benzyl-4,4'-Dimethoxystilbenyl Sulfenamide

A mixture of the compound prepared as described in Example 1 (1.74 g)and 1,3-bis(trimethylsilyl)urea (578 mg) in toluene (54 mL) was heatedto reflux. After 1.5 hours, the reaction was allowed to cool to roomtemperature, and treated with benzylamine (0.575 mL). After anadditional two hours, the reaction solution was evaporated to dryness togive a 7:1 mixture E/Z of regioisomers of the title compounds. Thisresidual mixture was purified using silica-gel flash chromatography,eluting with a mixture of ethyl acetate/hexane (7:1), to give 1.06 g ofthe title compounds as a 6:1 mixture of E/Z regioisomers.

Analysis calculated for C₂₃ H₂₃ NO₂ S: C, 73.18; H, 6.14; N, 3.71.Found: C, 73.16; H, 6.18; N, 3.50

E Isomer: ¹ H NMR (d₆ -benzene): δ7.41 (d, 2H), 7.13 (d, 2H), 7.12-7.03(m, 5H), 6.87 (s, 1H), 6.71 (d, 2H), 6.59 (d, 2H), 3.89 (d, 2H), 3.23(s, 3H), 3.20 (s, 3H), 2.71 (t, 1H). ¹³ C NMR (d₆ -benzene): δ159.98,158.91, 140.53, 139.77, 131.45, 130.50, 129.87, 128.77, 128.66, 128.59,127.53, 123.10, 114.74, 114.02, 56.14, 54.69, 54.64.

Z Isomer: ¹ H NMR (d₆ -benzene): δ7.59 (d, 2H), 7.53 (d, 2H), 7.01-6.91(m, 5H), 6.83 (s, 1H), 6.79 (d, 2H), 6.77 (d, 2H), 3.62 (d, 2H), 3.31(s, 3H), 3.27 (s, 3H), 2.82 (t, 1H). ¹³ C NMR (d₆ -benzene): δ160.05,159.14, 140.48, 139.27, 132.50, 131.32, 130.04, 129.86, 128.87, 128.58,128.46, 127.49, 114.48, 114.00, 56.23, 54.90, 54.78.

EXAMPLE 8 6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophene

A solution of p-toluenesulfonic acid monohydrate (552 mg) was added totoluene (15 mL) and heated to reflux, and water was removed by allowingit to collect in a Dean-Stark trap. This refluxing solution was treatedwith a solution of the regioisomeric compounds prepared as described inExample 4 (523 mg) in toluene (15 mL) over 15 minutes. Upon completeaddition, an aliquot was removed for HPLC analysis. This analysis showeda 46.6% in situ yield of the title compound.

EXAMPLE 9 6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophene

A solution of p-toluenesulfonic acid monohydrate (1.26 g) in toluene (20mL) was heated to reflux, and water was removed by allowing it tocollect in a Dean-Stark trap. A solution of the regioisomeric compoundsprepared as described in Example 6 (650 mg) in toluene (9 mL) was addedto the refluxing acid solution over 1.8 hours. The reaction solution wastreated with ethanol (10 mL), and the resulting mixture allowed to coolto room temperature. The resulting slurry was stirred at roomtemperature. After about 18 hours, the mixture was cooled to about 5°C., and filtered to give 290 mg of the title compound. Melting point199°-200° C.

¹ H NMR (d₆ -DMSO): δ7.67 (d, 1H), 7.64 (d, 2H), 7.61 (s, 1H), 7.52 (d,1H), 7.01 (d, 2H), 6.98 (dd, 1H), 3.81 (s, 3H), 3.79 (s, 3H).

Analysis calculated for C₁₆ H₁₄ O₂ S: C, 71.09; H, 5.22. Found: C,71.09; H, 5.27.

EXAMPLE 10 E andZ-3-(4,4'-Dimethoxystilbenylsulfide)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene

A solution of p-toluenesulfonic acid monohydrate (552 mg) in toluene(111 mL) was heated to reflux, and water was removed by allowing it tocollect in a Dean-Stark trap. A solution of the compound prepared asdescribed in Example 1 (10 g) in toluene (34 mL) was added to therefluxing acid solution over six hours. After an additional two hours,the mixture was cooled to 0° C. After an additional 18 hours, the coldmixture was filtered to remove the precipitated6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene. The filtrate wasextracted with an equal volume of saturated sodium bicarbonate solution.The organic phase was separated, dried over sodium sulfate, filtered,and concentrated in vacuo to give 4.8 g of an orange oil. This oil wasdivided into two parts and each purified using silica-gel flashchromatography, eluting with hexane/ethyl acetate (3.5:1). The fractionscontained in the desired regioisomers were concentrated to an oil. Thisoil was treated with diethyl ether to selectively crystallize theearly-eluting regioisomer (155 mg). The mother liquor from thesecrystallizations were enriched in the late-eluting regioisomer.

Early-eluting Isomer ¹ H NMR (CDCl₃): δ7.71 (d, 2H), 7.64 (d, 1H), 7.46(d, 2H), 7.06 (d, 1H), 6.94 (d, 2H), 6.92 (d, 2H), 6.90 (m, 1H), 6.85(d, 2H), 6.59 (s, 1H), 6.45 (d, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.80(s, 3H), 3.66 (s, 3H).

High resolution FABMS calculated for C₃₂ H₂₉ O₄ S₂ (MH⁺) 541.1507.Found: 541.1491.

Late-eluting Isomer ¹ H NMR (CDCl₃): δ7.90 (d, 1H), 7.62 (d, 2H), 7.24(1H), 7.08 (d, 2H), 7.02 (dd, 1H), 6.96 (d, 2H), 6.74-6.71 (d, 2H), 6.70(d, 2H), 6.55 (d, 2H), 6.21 (s, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.76(s, 3H), 3.67 (s, 3H).

FDMS: m/z=540 (m⁺)

EXAMPLE 11 6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophene

The compound (early-eluting isomer) prepared as described in Example 10(125 mg) was added to a refluxing solution of p-toluenesulfonic acidmonohydrate (4.2 mg) in toluene (1.5 mL). After six hours,methanesulfonic acid (7.5 μL) was added to the reaction mixture. Afteran additional hour, the reaction mixture was allowed to cool to roomtemperature. The resulting mixture was diluted with acetonitrile andassayed by HPLC, showing a 71.1% in situ yield of the title compound.

EXAMPLE 126-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiopheneHydrochloride 1,2-Dichloroethane Solvate

A. Preparation of Ethyl 4-(2-piperidinoethoxy)benzoate

A mixture of ethyl 4-hydroxybenzoate (8.31 g),1-(2-chloroethyl)piperidine monohydrochloride (10.13 g), potassiumcarbonate (16.59 g), and methyl ethyl ketone (60 mL) was heated to 80°C. After one hour, the mixture was cooled to about 55° C. and treatedwith additional 1-(2-chloroethyl)piperidine monohydrochloride (0.92 g).The resulting mixture was heated to 80° C. The reaction was monitored bythin layer chromatography (TLC), using silica-gel plates and ethylacetate/acetonitrile/triethylamine (10:6:1, v/v). Additional portions of1-(2-chloroethyl)piperidine hydrochloride are added until the starting4-hydroxybenzoate ester is consumed. Upon complete reaction, thereaction mixture was treated with water (60 mL) and allowed to cool toroom temperature. The aqueous layer was discarded and the organic layerconcentrated in vacuo at 40° C. and 40 mm Hg. The resulting oil was usedin the next step without further purification.

B. Preparation of 4-(2-Piperidinoethoxy)benzoic Acid Hydrochloride

A solution of the compound prepared as described in Example 12A (about13.87 g) in methanol (30 mL) was treated with 5N sodium hydroxide (15mL), and heated to 40° C. After 41/2 hours, water (40 mL) was added. Theresulting mixture was cooled to 5°-10° C., and concentrated hydrochloricacid (18 mL) was added slowly. The title compound crystallized duringacidification. This crystalline product was collected by filtration, anddried in vacuo at 40°-50° C. to give 83% yield of the title compound.Melting point 270°-271° C.

C. Preparation of 4-(2-Piperidinoethoxy)benzoyl Chloride Hydrochloride

A solution of the compound prepared as described in Example 12B (30.01g) and dimethylformamide (2 mL) in methylene chloride (500 mL) wastreated with oxalyl chloride (10.5 mL) over a 30-35 minute period. Afterstirring for about 18 hours, the reaction was assayed for completion byHPLC analysis. Additional oxalyl chloride may be added to the reactionif the starting carboxylic acid is present. Upon completion, thereaction solution was evaporated to dryness in vacuo. The residue wasdissolved in methylene chloride (200 mL), and the resulting solutionevaporated to dryness. This dissolution/evaporation procedure wasrepeated to give the title compound as a solid.

D. Preparation of6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiopheneHydrochloride 1,2-Dichloroethane Solvate

A mixture of the compound prepared as described in Example 8 or 9 (2.92g), the compound prepared as described in Example 12C (3.45 g), and1,2-dichloroethane (52 mL) was cooled to about 0° C. Boron trichloridegas was condensed into a cold graduated cylinder (2.8 mL), and added tothe cold mixture described above. After eight hours at 0° C., thereaction mixture was treated with additional boron trichloride (2.8 mL).The resulting solution was heated to 35° C. After 16 hours, the reactionwas complete.

Methanol (30 mL) was treated with the reaction mixture from above over a20-minute period, causing the methanol to reflux. The resulting slurrywas stirred at 25° C. After one hour, the crystalline product wasfiltered, washed with cold methanol (8 mL), and dried at 40° C. in vacuoto give 5.14 g of the title compound. Melting point 225° C.

Potency (HPLC): 86.8%

1,2-Dichloroethane (gas chromatography): 6.5%

EXAMPLE 13 6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophene

A solution of p-toluenesulfonic acid monohydrate (1.05 g) in toluene (20mL) was heated to reflux, and water was removed by allowing it tocollect in a Dean-Stark trap. A solution of the regioisomeric compoundsprepared as described in Example 7 (780 mg) in toluene (9 mL) was addedto the refluxing acid solution over ten minutes. After one hour, thereaction solution was treated with ethanol (10 mL), and the resultingmixture allowed to cool to room temperature. The resulting slurry wasstirred at room temperature. After about 18 hours, the mixture wasfiltered to give 149 mg of the title compound. Melting point 199°-200°C.

Analysis calculated for C₁₆ H₁₄ O₂ S: C, 71.09; H, 5.22.

Found: C, 71.05; H, 5.22.

EXAMPLE 14 E and Z-4,4'-Dimethoxystilbenyl Ethyl Disulfide

A solution of the regioisomeric compounds prepared as described inExample 4 (1.83 g) in toluene (54 mL) was treated with ethanethiol(0.433 mL) and triethylamine (0.715 mL). After about 2.5 hours at roomtemperature, the reaction solution was evaporated to dryness in vacuo togive a mixture of regioisomers. The residue was purified usingsilica-gel chromatography, eluting with ethyl acetate/hexane (9:1), togive 1.14 g of a 5.7:1 mixture of E/Z regioisomers of the titlecompounds.

Analysis calculated for C₁₈ H₂₀ O₂ S₂ : C, 65.03; H, 6.06.

Found: C, 65.32; H, 6.28.

E Isomer: ¹ H NMR (d₆ -benzene): δ7.35 (d, 2H), 7.19 (s, 1H), 7.05 (d,2H), 6.72 (d, 2H), 6.54 (d, 2H), 3.21 (s, 3H), 3.14 (s, 3H), 2.39 (q,2H), 1.09 (t, 3H). ¹³ C NMR (d₆ -benzene): δ160.09, 159.16, 135.95,131.71, 130.61, 130.16, 129.48, 126.88, 114.54, 113.99, 54.64, 54.61,32.29, 14.33.

Z Isomer: ¹ H NMR (d₆ -benzene): δ7.67 (d, 2H), 7.58 (d, 2H), 6.90 (s,1H), 6.83 (d, 2H), 6.80 (d, 2H), 3.30 (s, 3H), 3.28 (s, 3H), 2.26 (q,2H), 0.94 (t, 3H). ¹³ C NMR (d₆ -benzene): δ159.98, 159.53, 137.58,134.03, 132.79, 131.69, 130.45, 113.91, 113.87, 54.79, 54.73, 32.61,14.25.

EXAMPLE 15 6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophene

A solution of p-toluenesulfonic acid monohydrate (1.21 g) in toluene (20mL) was heated to reflux, and water was removed by allowing it tocollect in a Dean-Stark trap. A solution of the regioisomeric compoundsprepared as described in Example 14 (685 mg, 5.7:1 regioisomericmixture) in toluene (9 mL) was added to the refluxing acid solution over1.8 hours. An aliquot of the mixture was analyzed by HPLC, showing a23.2% in situ yield of the title compound.

We claim:
 1. A process for preparing a compound of the formula ##STR19##wherein: R₁ is hydrogen, C₁ -C₄ alkoxy, arylalkoxy, halo, or amino;andR₂ is hydrogen, C₁ -C₄ alkoxy, arylalkoxy, halo, or amino; whichcomprises cyclizing in the presence of an acid catalyst a compound ofthe formula ##STR20## wherein: R₁ and R₂ are as defined above; R₄ isOSi(R)₃, NR₅ R₆, or SR₈ ; each R is independently C₁ -C₆ alkyl, aryl, orarylalkyl; R₅ and R₆ are independently hydrogen, C₁ -C₆ alkyl,arylalkyl, or aryl; or R₅ and R₆ together with the nitrogen atom form aring selected from piperidine, pyrrolidine, morpholine, andhexamethylimine; and R₈ is C₁ -C₆ alkyl, aryl, or arylalkyl.
 2. Theprocess of claim 1 wherein:R₁ is hydrogen, C₁ -C₄ alkoxy, or arylalkoxy;and R₂ is hydrogen, C₁ -C₄ alkoxy, or arylalkoxy.
 3. The process ofclaim 2 wherein the acid catalyst is selected from the group consistingof methanesulfonic acid, benzenesulfonic acid, 1-naphthalenesulfonicacid, 1-butanesulfonic acid, ethanesulfonic acid, 4-ethylbenzenesulfonicacid, 1-hexanesulfonic acid, 1,5-naphthalenedisulfonic acid,1-octanesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonicacid, p-toluenesulfonic acid, Nafion®, Amberlyst®, and Amberlite®. 4.The process of claim 3 wherein the acid catalyst is selected form thegroup consisting of methanesulfonic acid, benzenesulfonic acid,camphorsulfonic acid, p-toluenesulfonic acid, Nafion®, Amberlyst®, andAmberlite®.
 5. The process of claim 4 wherein the acid catalyst isselected from the group consisting of methanesulfonic acid,p-toluenesulfonic acid, Nafion®, Amberlyst®, and Amberlite®.
 6. Theprocess of claim 5 wherein:R₄ is OSi(R)₃ ; and each R is independentlyC₁ -C₆ alkyl, aryl, or arylalkyl.
 7. The process of claim 6 wherein R₄is OTMS, OTES, OTIPS, ODMIPS, ODEIPS, OTDS, OTBDMS, OTBDPS, OTBS, OTPS,ODPMS, or OTBMPS.
 8. The process of claim 7 wherein R₄ is OTMS, OTES,ODMIPS, ODEIPS, OTBDMS, OTBS, or OTPS.
 9. The process of claim 8 whereinR₄ is OTMS.
 10. The process of claim 9 wherein the acid catalyst isp-toluenesulfonic acid.
 11. The process of claim 5 wherein:R₄ is NR₅ R₆; and R₅ and R₆ are independently hydrogen, C₁ -C₆ alkyl, arylalkyl, oraryl; or R₅ and R₆ together with the nitrogen atom form a ring selectedfrom piperidine, pyrrolidine, morpholine, and hexamethylimine.
 12. Theprocess of claim 11 wherein R₅ and R₆ are independently hydrogen, C₁ -C₆alkyl, or arylalkyl; or R₅ and R₆ together with the nitrogen atom form aring selected from piperidine and pyrrolidine.
 13. The process of claim12 wherein R₅ and R₆ are methyl, or R₅ is hydrogen and R₆ is benzyl. 14.The process of claim 13 wherein the acid catalyst is p-toluenesulfonicacid.
 15. The process of claim 5 wherein:R₄ is SR₈ ; and R₈ is C₁ -C₆alkyl, aryl, or arylalkyl.
 16. The process of claim 15 wherein R₈ is C₁-C₆ alkyl or arylalkyl.
 17. The process of claim 16 wherein R₈ is C₁ -C₆alkyl.
 18. The process of claim 17 wherein the acid catalyst isp-toluenesulfonic acid.
 19. A process for preparing a compound of theformula ##STR21## wherein: R₁ is hydrogen, C₁ -C₄ alkoxy, arylalkoxy,halo, amino; andR₂ is hydrogen, C₁ -C₄ alkoxy, arylalkoxy, halo, amino;which comprising treating a compound of the formula ##STR22## wherein R₁and R₂ are as defined above, with an acid.
 20. The process of claim 19wherein:R₁ is hydrogen, C₁ -C₄ alkoxy, or arylalkoxy; and R₂ ishydrogen, C₁ -C₄ alkoxy, or arylalkoxy.
 21. The process of claim 20wherein the acid catalyst is selected form the group consisting ofmethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid,p-toluenesulfonic acid, Nafion®, Amberlyst®, and Amberlite®.
 22. Theprocess of claim 21 wherein R₁ and R₂ are C₁ -C₄ alkoxy.
 23. The processof claim 22 wherein the acid catalyst is p-toluenesulfonic acid.
 24. Theprocess of claim 23 wherein R₁ and R₂ are methoxy.
 25. A process forpreparing a compound of the formula ##STR23## wherein: R₉ is hydrogen,halo, amino, or hydroxyl;R₁₀ is hydrogen, halo, amino, or hydroxyl; R₁₁and R₁₂ are independently C₁ -C₄ alkyl, or R₁₁ and R₁₂ together with theadjacent nitrogen atom form a heterocyclic ring selected from the groupconsisting of pyrrolidino, piperidino, hexamethyleneimino, andmorpholino; and HX is HCl or HBr; comprising the steps of: (a) cyclizingin the presence of an acid catalyst a compound of the formula ##STR24##wherein: R₁ is hydrogen, C₁ -C₄ alkoxy, arylalkoxy, halo, or amino; R₂is hydrogen, C₁ -C₄ alkoxy, arylalkoxy, halo, or amino; and R₄ isOSi(R)₃, NR₅ R₆, or SR₈ ; each R is independently C₁ -C₆ alkyl, aryl, orarylalkyl; R₅ and R₆ are independently hydrogen, C₁ -C₆ alkyl, or aryl,or R₅ and R₆ together with the nitrogen atom form a ring selected frompiperidine, pyrrolidine, morpholine, and hexamethylimine; and R₈ is C₁-C₆ alkyl, aryl, or arylalkyl; to prepare a benzothiophene compound ofthe formula ##STR25## wherein R₁ and R₂ are as defined above; (b)acylating said benzothiophene compound with an acylating agent of theformula ##STR26## wherein: R₁₁, R₁₂, and HX are as defined previously;and R₁₃ is chloro, bromo, or hydroxyl; in the presence of BX'₃, whereinX' is chloro or bromo; and (c) when R₁ and/or R₂ is C₁ -C₄ alkoxy orarylalkoxy, dealkylating one or more phenolic groups of the acylationproduct of step (b) by reacting with additional BX'₃, wherein X' is asdefined above.